High-resolution HLA class II sequencing of Swedish multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic neurological disease believed to be caused by autoimmune pathogenesis. The aetiology is likely explained by a complex interplay between inherited and environmental factors. Genetic investigations into MS have been conducted for over 50 years, yielding >100 associations to date. Globally, the strongest linkage is with the human leukocyte antigen (HLA) HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 haplotype. Here, high-resolution sequencing of HLA was used to determine the alleles of DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 as well as their extended haplotypes and genotypes in 100 Swedish MS patients. Results were compared to 636 population controls. The heterogeneity in HLA associations with MS was demonstrated; among 100 patients, 69 extended HLA-DR-DQ genotypes were found. Three extended HLA-DR-DQ genotypes were found to be correlated to MS; HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 haplotype together with (A) HLA-DRB4*01:01:01//DRB4*01:01:01:01-DRB1*07:01:01-DQA1*02:01//02:01:01-DQB1*02:02:01, (B) HLA-DRBX*null-DRB1*08:01:01-DQA1*04:01:01-DQB1*04:02:01, and (C) HLA-DRB3*01:01:02-DRB1*03:01:01-DQA1*05:01:01-DQB1*02:01:01. At the allelic level, HLA-DRB3*01:01:02 was considered protective against MS. However, when combined with HLA-DRB3*01:01:02-DRB1*03:01:01-DQA1*05:01:01-DQB1*02:01:01, this extended haplotype was considered a predisposing risk factor. This highlights the limitations as included with investigations of single alleles relative to those of extended haplotypes/genotypes. In conclusion, with 69 genotypes presented among 100 patients, high-resolution sequencing was conducted to underscore the wide polymorphisms present among MS patients. Additional studies in larger cohorts will be of importance to define MS among the patient group not associated with HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01.

Characteristics and outcomes of stroke hospitalizations in patients with sickle cell disease and moyamoya syndrome.

OBJECTIVES: Stroke is the leading cause of death in patients with Sickle cell disease (SCD). Here, we detail the burden of Moyamoya syndrome (MMS) as a cause of stroke in patients with SCD. MATERIALS AND METHODS: A review of SCD-related hospital discharges was conducted utilizing the National Inpatient Sample. Rates of stroke hospitalization, risk factors, procedures, and outcomes were compared between patients with SCD-MMS and SCD alone. Univariate analyses including T-test, Wilcoxon Rank-Sum test, Chi-square were performed to compare risk factors and outcomes. Multivariable regression was used to identify predictors of stroke unique to each population. RESULTS: Stroke occurred in 9.8% of SCD-MMS hospitalizations versus 0.5% of those involving patients with SCD alone (OR = 20.71, p < 0.001). Patients with SCD-MMS developed stroke at younger ages and with fewer comorbidities compared to those with SCD alone. Stroke hospitalizations in SCD-MMS involved a greater number of procedures (90.5% vs. 79.3%, p = 0.007), but were more likely to result in favorable discharge (58.5% vs. 44.2%, p = 0.005). The presence of anemia during hospitalization was a significant risk factor for stroke in both cohorts. Long-term antiplatelet use was protective against stroke (OR = 0.42, p = 0.008) only in the SCD-MMS cohort. CONCLUSIONS: MMS confers a 20-fold increased risk of stroke among patients with SCD and appears to be an important cause of recurrent stroke in this population. Anemia is one of the most significant risk factors for stroke, while antiplatelet use appears to confer a protective benefit.

Experimental animal models for moyamoya disease and treatment: a pathogenesis-oriented scoping review.

OBJECTIVE: Moyamoya disease (MMD) is an intracranial steno-occlusive pathology characterized by progressive narrowing of proximal large vessels, including the terminal internal carotid arteries (ICAs), middle cerebral arteries, or anterior cerebral arteries. Named for the "puff of smoke" appearance of the anomalous vascularization visualized on cerebral angiography, MMD lacks a well-defined etiology, although significant insights have been made, including the identification of a susceptibility gene, RNF213, in humans with the disease. A limitation to advancing the understanding and treatment of MMD has been the lack of experimental animal models that authentically reflect the clinical pathogenesis. In an effort to analyze characteristics of currently available models and identify strategies for future model generation, the authors performed a scoping review of experimental animal models that have been used to study MMD. METHODS: A systematic search of PubMed, Web of Science, and Scopus was performed to identify articles describing animal models used to study MMD. Additional articles were identified via citation searching. Study selection and data extraction were performed by two independent reviewers based on defined inclusion and exclusion criteria. RESULTS: A total of 44 articles were included for full-text review. The methods used to generate these animal models were broadly classified as surgical (n = 25, 56.8%), immunological (n = 7, 15.9%), genetic (n = 6, 13.6%), or a combination (n = 6, 13.6%). Surgical models typically involved permanent ligation of one or both of the common carotid arteries or ICAs to produce chronic cerebral hypoperfusion. Genetic models utilized known MMD or cerebrovascular disease-related genes, such as RNF213 or ACTA2, to induce heritable cerebral vasculopathy. Finally, immunological models attempted to induce vasculitis-type pathology by recapitulating the inflammatory milieu thought to underlie MMD. CONCLUSIONS: Models generated for MMD have involved three general approaches: surgical, immunological, and genetic. Although each reflects a key aspect of MMD pathogenesis, the failure of any individual model to recapitulate the development, progression, and consequences of the disease underscores the importance of future work in developing a multietiology model.

Multiple cerebral hemorrhages in sepsis-disseminated intravascular coagulation versus septic embolism: An image report.

BACKGROUND: Septic emboli are commonly attributed to infective endocarditis and can present with a variety of symptoms including altered mental status and focal neurological deficits. Here, we reviewed images of septic emboli with hemorrhagic conversion in a patient with sepsis and a psoas abscess. We aim to show the classical image findings in septic embolism to brain, which is sparsely described in literature and the report differentiates the septic embolism from disseminated intravascular coagulation which can present with almost identical image findings. CASE DESCRIPTION: A 53-year-old male patient who was operated on for a right inguinal hernia developed a postoperative wound infection 2 weeks after surgery and was started on IV antibiotics. Despite medical management, his infection did not improve, prompting a computed tomography (CT) scan which revealed a psoas abscess. The abscess was drained, and antibiotics continued. A few days later, he developed altered sensorium prompting a head CT which revealed septic emboli and hemorrhage at the gray-white junction. Cultures grew multidrug-resistant Escherichia coli; the patient was treated with IV tigecycline and improved over the following 4 weeks. CONCLUSION: In patients with a known ongoing infectious process with hemodynamic stability who develop altered mental status in the setting of a normal coagulation profile, D-dimer, positive blood cultures, and absent signs of multiorgan failure, a diagnosis of septic emboli should be entertained. Although CT can reveal macrobleeds, MRI is more sensitive in confirming cerebral microbleeds. Thus, patients in sepsis with unexplained altered sensorium should undergo an MRI of the brain to rule out septic emboli and microbleeds.

Screening for autoantibody targets in post-vaccination narcolepsy using proteome arrays.

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a specific loss of hypocretin-producing neurons. The incidence of NT1 increased in Sweden, Finland and Norway following Pandemrix®-vaccination, initiated to prevent the 2009 influenza pandemic. The pathogenesis of NT1 is poorly understood, and causal links to vaccination are yet to be clarified. The strong association with Human leukocyte antigen (HLA) DQB1*06:02 suggests an autoimmune pathogenesis, but proposed autoantigens remain controversial. We used a two-step approach to identify autoantigens in patients that acquired NT1 after Pandemrix®-vaccination. Using arrays of more than 9000 full-length human proteins, we screened the sera of 10 patients and 24 healthy subjects for autoantibodies. Identified candidate antigens were expressed in vitro to enable validation studies with radiobinding assays (RBA). The validation cohort included NT1 patients (n = 39), their first-degree relatives (FDR) (n = 66), population controls (n = 188), and disease controls representing multiple sclerosis (n = 100) and FDR to type 1 diabetes patients (n = 41). Reactivity towards previously suggested NT1 autoantigen candidates including Tribbles homolog 2, Prostaglandin D2 receptor, Hypocretin receptor 2 and α-MSH/proopiomelanocortin was not replicated in the protein array screen. By comparing case to control signals, three novel candidate autoantigens were identified in the protein array screen; LOC401464, PARP3 and FAM63B. However, the RBA did not confirm elevated reactivity towards either of these proteins. In summary, three putative autoantigens in NT1 were identified by protein array screening. Autoantibodies against these candidates could not be verified with independent methods. Further studies are warranted to identify hypothetical autoantigens related to the pathogenesis of Pandemrix®-induced NT1.

The Origins of Eponymous Aneurysm Clips: A Review.

Aneurysm clips are indispensable tools in the armamentarium of vascular neurosurgeons. The history of the development of aneurysm clips is witness to ingenuity and tenacity in treating a potentially devastating disease. Few know the stories of their innovators and the inspiration behind their designs. Hence, we present this historical vignette in an attempt to shed more light on the pioneers who shaped the evolution of aneurysm clips as we know them. A comprehensive literature search was performed using PubMed, Google Scholar, Google Books, and library historical archives, as well as personal communications with relatives, colleagues, and institutions of the surgeon-designers. We present the following aneurysm clip innovators and chronicle their biographies and contributions: Herbert Olivecrona (1891-1980), Frank Mayfield (1908-1991), Charles Drake (1920-1998), Joseph McFadden (1920-present), Thoralf Sundt Jr. (1930-1992), William M. Lougheed (1923-2004), William B. Scoville (1906-1984), Milton D. Heifetz (1921-2015), Gazi Yasargil (1925-present), Kenichiro Sugita (1932-1994), and Robert Spetzler (1944-present). Although this compilation of eponymous clips is by no means complete, we hope that it provides an informative historical perspective and an inspiration for aspiring neurosurgeons. The history of aneurysm surgery, an entity once deemed inoperable, teaches us the importance of innovation in medicine.

HLA high-resolution typing by next-generation sequencing in Pandemrix-induced narcolepsy.

The incidence of narcolepsy type 1 (NT1) increased in Sweden following the 2009-2010 mass-vaccination with the influenza Pandemrix-vaccine. NT1 has been associated with Human leukocyte antigen (HLA) DQB1*06:02 but full high-resolution HLA-typing of all loci in vaccine-induced NT1 remains to be done. Therefore, here we performed HLA typing by sequencing HLA-DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 in 31 vaccine-associated NT1 patients and 66 of their first-degree relatives (FDR), and compared these data to 636 Swedish general population controls (GP). Previously reported disease-related alleles in the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 extended haplotype were increased in NT1 patients (34/62 haplotypes, 54.8%) compared to GP (194/1272 haplotypes, 15.3%, p = 6.17E-16). Indeed, this extended haplotype was found in 30/31 patients (96.8%) and 178/636 GP (28.0%). In total, 15 alleles, four extended haplotypes, and six genotypes were found to be increased or decreased in frequency among NT1 patients compared to GP. Among subjects with the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02-DQB1*06:02 haplotype, a second DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype (p = 2.02E-2), but not homozygosity for DRB1*15:01:01-DQB1*06:02:01 (p = 7.49E-1) conferred association to NT1. Alleles with increased frequency in DQA1*01:02:01 (p = 1.07E-2) and DQA1*03:02//*03:03:01 (p = 3.26E-2), as well as with decreased frequency in DRB3*01:01:02 (p = 8.09E-3), DRB1*03:01:01 (p = 1.40E-2), and DQB1*02:01:01 (p = 1.40E-2) were found among patients compared to their FDR. High-resolution HLA sequencing in Pandemrix-associated NT1 confirmed the strong association with the DQB1*06:02:01-containing haplotype but also revealed an increased association to the not previously reported extended HLA-DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype. High-resolution HLA typing should prove useful in dissecting the immunological mechanisms of vaccination-associated NT1.

Autoantibodies in Pandemrix®-induced narcolepsy: Nine candidate autoantigens fail the conformational autoantibody test.

Study objectives: Narcolepsy type 1 (NT1) is a chronic sleep disorder characterized by loss of hypocretin-producing neurons. Increased NT1 incidence was observed in Sweden following mass-vaccination with Pandemrix®. Genetic association to HLA DQB1*06:02 implies an autoimmune origin, but target autoantigen remains unknown. Candidate autoantigens for NT1 have previously been identified in solid-phase immunoassays, while autoantibodies against conformation-dependent epitopes are better detected in radiobinding assays. The aims are to determine autoantibody levels against nine candidate autoantigens representing (1) proteins of the hypocretin transmitter system; Preprohypocretin (ppHypocretin), Hypocretin peptides 1 and 2 (HCRT1 and HCRT2) and Hypocretin receptor 2 (HCRTR2); (2) proteins previously associated with NT1; Tribbles homologue 2 (TRIB2), Pro-opiomelanocortin/alpha-melanocyte-stimulating-hormone (POMC/α-MSH) and Prostaglandin D2 Receptor DP1 (DP1); (3) proteins suggested as autoantigens for multiple sclerosis (another HLA DQB1*06:02-associated neurological disease); ATP-dependent Inwardly Rectifying Potassium Channel Kir4.1 (KIR4.1) and Calcium-activated chloride channel Anoctamin 2 (ANO2). Methods: Serum from post-Pandemrix® NT1 patients (n = 31) and their healthy first-degree relatives (n = 66) were tested for autoantibody levels in radiobinding assays separating autoantibody bound from free labelled antigen with Protein A-Sepharose. 125I-labelled HCRT1 and HCRT2 were commercially available while 35S-methionine-labelled ppHypocretin, HCRTR2, TRIB2, α-MSH/POMC, DP1, KIR4.1 or ANO2 was prepared by in vitro transcription translation of respective cDNA. In-house standards were used to express data in arbitrary Units/ml (U/ml). Results: All radiolabelled autoantigens were detected in a concentration-dependent manner by respective standard sera. Levels of autoantibodies in the NT1 patients did not differ from healthy first-degree relatives in any of the nine candidate autoantigens. Conclusions: None of the nine labelled proteins proposed to be autoantigens were detected in the radiobinding assays for conformation-dependent autoantibodies. The results emphasise the need of further studies to identify autoantigen(s) and clarify the mechanisms in Pandemrix®-induced NT1.

The relationships between improvements in daytime sleepiness, fatigue and depression and psychomotor vigilance task testing with CPAP use in patients with obstructive sleep apnea.

OBJECTIVE: The purpose of this study was to determine if the subjective improvements in daytime sleepiness, fatigue and depression experienced by patients with obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) therapy predict an objective improvement in vigilance, and whether patients with mild-to-moderate OSA differ from patients with severe OSA in this regard. METHODS: A total of 182 patients underwent psychomotor vigilance task (PVT) testing and measurements of subjective daytime sleepiness, fatigue and depression at baseline and after a minimum of one month of adherent CPAP use at an adequate pressure. RESULTS: Patients with both mild-to-moderate (n = 92) and severe (n = 90) OSA experienced improvements in subjective daytime sleepiness, fatigue and depression, but objective improvement in vigilance was only seen in patients with severe OSA. In patients with severe OSA, while a correlation was found between improvements in daytime sleepiness and some PVT parameters, changes in subjective daytime sleepiness, fatigue and depression scores were not predictive of objective improvement in vigilance while controlling for all these subjective symptoms and for age, gender, body mass index, apnea-hypopnea index/respiratory event index and total sleep time/total recording time with pulse oximetry below 90%. CONCLUSIONS: We found no predictive relationship between subjective improvements in daytime sleepiness, fatigue and depression and objective vigilance with CPAP use in patients with OSA. These results suggest that subjective complaints of daytime impairment and objective measures of vigilance in patients with OSA should be assessed separately while evaluating the efficacy of CPAP therapy on daytime functioning.